The goal of this project is to conduct clinical trials that will show that photodynamic therapy (PDT) has a pivotal role in improving tumor response and quality of life (QoL) for patients with head and neck squamous cell carcinoma (HNSCC). To that end we will designed three trials. The first trial is a randomized three-center Phase II study for patients with T1/T2 N0 squamous cell carcinoma (SCC) of the oral cavity. Surgery, the preferred therapy, is often associated with loss of organ function. HPPH mediated PDT has shown promising results in treating these tumors without loss of organ function. We hypothesize that PDT with HPPH is an organ sparing therapy that has the potential to effectively treat patients with T1/T2 N0 SCC of the oral cavity, in comparison to standard surgery. The second trial is a randomized three-center Phase II study for patients with locally advanced recurrent HNSCC that have failed radiation therapy. The SoC chemotherapy (platinum base, 5-fluorouracil plus Cetuximab) yields objective response rates of 36%, at best. A nonrandomized Phase II trial with interstitial PDT (I-PDT) has shown promise by achieving overall response rate of 74% in the treatment of locally advanced recurrent HNSCC. We hypothesize that I-PDT with SoC chemotherapy will improve tumor response in patients with locally advanced recurrent HNSCC that failed radiation therapy, in comparison to SoC chemotherapy alone. The third trial is a Phase I vaccine study testing the safety of a PDT- generated vaccine for patients with HNSCC and positive lymph nodes, which is the strongest prognosis for poor clinical outcomes. We hypothesize that surgical resection of HNSCC followed by vaccination with PDT generated vaccine can be performed safely and will enhance anti-tumor T cell activation and responses against HNSCC tumors. Our hypotheses will be tested in the following Specific Aims: 1. To perform a randomized multi-center Phase II trial with HPPH-PDT for the treatment of T1/T2 N0 SCC of the oral cavity. 2. To perform a randomized multi-center Phase II trial with HPPH mediated I-PDT and SoC chemotherapy for the treatment of patients with locally advanced recurrent HNSCC that failed radiation therapy. 3. To perform a Phase I combination trial of surgery followed by HPPH PDT generated vaccine for the treatment of patients with HNSCC and positive lymph nodes.